Abstract 2328: Interrogating the anti-cancer effects of co-enzyme Q10 (CoQ10) identifies metabolic and mitochondrial apoptotic responses as primary mechanisms in squamous cell carcinoma model

Abstract Houttuynia cordata Thunb (HCT) is a medicinal and edible herb which has beneficial effects on various diseases due to its diuretic, anti-inflammatory, anti-oxidative, anti-microbial, anti-viral, anti-cancer and anti-diabetic properties. Most of reports of its anti-cancer activity were conducted in vitro, and its effects on cutaneous squamous cell carcinoma (SCC) has not been investigated yet. Using DMBA/TPA induced SCC mice model, we found that topical treatment by HCT, as well as its bioactive ingredient monomer, efficiently inhibited tumor growth. Mechanistically, we found tumor infiltrating CD4+, Foxp3+ T regulatory cells (Tregs) were significantly reduced and CD8+/Treg cells ratio was largely increased in tumors after HCT treatment. In addition, several chemokines which recruited immune cells were largely reduced when SCC cancer cells were treated by HCT in vitro. Our results demonstrate the therapeutic effects of HCT on cutaneous SCC and indicate it might inhibit cancer through regulating tumor infiltrating lymphocytes and the tumor immune microenvironments.

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Repression of BET activity sensitizes oral squamous cell carcinoma to PARP inhibition via inhibiting DNA homologous recombination and immune inhibition

10.21203/rs.3.rs-26946/v2 ◽

2021 ◽

Author(s):

Dongdong Tong ◽

Xin Zhang ◽

Fenghe Zhang ◽

xiaojing Liu

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Parp Inhibitor ◽

Cell Cycle Distribution ◽

Bet Inhibitor ◽

Anti Cancer

Abstract Objective: To investigate the therapeutic resistance mechanism of oral squamous cell carcinoma (OSCC) to the PARP inhibitor olaparib and explore the combination with the BET inhibitor JQ1 to enhance its treatment effects. Material and Methods: Cell proliferation, apoptosis and cell cycle distribution were evaluated. Levels of relevant factors were determined by quantitative real-time PCR, western blot and immunofluorescence. The effect of the combination treatment on xenograft OSCC mouse model was examined.Results: Cal27 cells were more sensitive to the PARP inhibitor olaparib than Scc25 cells. Functional assays demonstrated that olaparib induced HR repair and upregulated PD-L1 expression, which results in drug resistance of OSCC to olaparib. Variations of these factors in the two cell lines may explain different sensitivity to olaparib. Moreover, the JQ1 BET inhibitor and olaparib synergistically exhibited anti-cancer effects in OSCC in vitro and in vivo and inhibited essential HR repair factors RAD51, BRCA1, and TOPBP1 through the ATR/CHK1 pathway and immune suppression mediated by the PD-L1 pathway.Conclusions: Elevated HR and PD-L1 are involved in resistance mechanisms of OSCC to olaparib, attenuating its anti-tumor effects. Our results suggest that the strong synergistic anti-cancer effects of the combination of olaparib with the JQ1 BET inhibitor in OSCC in vitro and in vivo may be via suppression of the ATR/CHK1-mediated DNA damage response and PD-L1-related immune escape, indicating this combination strategy as a possible therapeutic approach for OSCC.

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Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

Forests ◽

10.3390/f11010008 ◽

2019 ◽

Vol 11 (1) ◽

pp. 8 ◽

Cited By ~ 2

Author(s):

Goo Yoon ◽

Mee-Hyun Lee ◽

Ah-Won Kwak ◽

Ha-Na Oh ◽

Seung-Sik Cho ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Er Stress ◽

Cell Carcinoma ◽

Squamous Cell ◽

Podophyllum Peltatum ◽

Phase Arrest ◽

Anti Cancer ◽

M Phase ◽

Stress Dependent

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in East Asia and is the seventh leading cause of cancer deaths. Podophyllotoxin (PT), a cyclolignan isolated from podophyllum peltatum, exhibits anti-cancer effects at the cellular level. This study investigated the underlying mechanism of anti-cancer effects induced by PT in ESCC cells. Exposure to increasing concentrations of PT led to a significant decrease in the growth and anchorage-independent colony numbers of ESCC cells. PT showed high anticancer efficacy against a panel of four types of ESCC cells, including KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510 by IC50 at values ranges from 0.17 to 0.3 μM. We also found that PT treatment induced G2/M phase arrest in the cell cycle and accumulation of the sub-G1 population, as well as apoptosis. Exposure to PT triggered a significant synthesis of reactive oxygen species (ROS), a loss of mitochondrial membrane potential (MMP), and activation of various caspases. Furthermore, PT increased the levels of phosphorylated c-Jun N-terminal kinase (JNK), p38, and the expression of Endoplasmic reticulum (ER) stress marker proteins via ROS generation. An increase in the level of pro-apoptotic proteins and a reduction in the anti-apoptotic protein level induced ESCC cell death via the loss of MMP. Additionally, the release of cytochrome c into the cytosol with Apaf-1 induced the activation of multi-caspases. In conclusion, our results revealed that PT resulted in apoptosis of ESCC cells by modulating ROS-mediated mitochondrial and ER stress-dependent mechanisms. Therefore, PT is a promising therapeutic candidate as an anti-cancer drug against ESCC for clinical use.

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